Neuromuscular Research Articles

Peripheral glia and neurons jointly regulate activity-induced synaptic remodeling at the Drosophila neuromuscular junction.

In the nervous system, reliable communication depends on the ability of neurons to adaptively remodel their synaptic structure and function in response to changes in neuronal activity. While neurons are the main drivers of synaptic plasticity, glial cells are increasingly recognized for their roles as active modulators. However, the underlying molecular mechanisms remain unclear. Here, using Drosophila neuromuscular junction as a model system for a tripartite synapse, we show that peripheral glial cells collaborate with neurons at the NMJ to regulate activity-induced synaptic remodeling, in part through a protein called shriveled (Shv). Shv is an activator of integrin signaling previously shown to be released by neurons during intense stimulation at the fly NMJ to regulate activity-induced synaptic remodeling. We demonstrate that Shv is also present in peripheral glia, and glial Shv is both necessary and sufficient for synaptic remodeling. However, unlike neuronal Shv, glial Shv does not activate integrin signaling at the NMJ. Instead, it regulates synaptic plasticity in two ways: 1) maintaining the extracellular balance of neuronal Shv proteins to regulate integrin signaling, and 2) controlling ambient extracellular glutamate concentration to regulate postsynaptic glutamate receptor abundance. Loss of glial cells showed the same phenotype as loss of Shv in glia. Together, these results reveal that neurons and glial cells homeostatically regulate extracellular Shv protein levels to control activity-induced synaptic remodeling. Additionally, peripheral glia maintains postsynaptic glutamate receptor abundance and contribute to activity-induced synaptic remodeling by regulating ambient glutamate concentration at the fly NMJ.

CHCHD10P80L knock-in zebrafish display a mild ALS-like phenotype

Mutations in the nuclear-encoded mitochondrial gene CHCHD10 have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10P80L variant (zebrafish: Chchd10P83L). Larval chchd10P83L/P83L fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (chchd10−/−). Adult, 11-month old chchd10P83L/P83L zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of chchd10P83L/P83L zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to chchd2−/− adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our chchd10P83L/P83L model. The findings presented here, suggest that the CHCHD10P80L variant confers an ALS-like phenotype when expressed in zebrafish.

Distinct input-specific mechanisms enable presynaptic homeostatic plasticity.

Synapses are endowed with the flexibility to change through experience, but must be sufficiently stable to last a lifetime. This tension is illustrated at the Drosophila neuromuscular junction (NMJ), where two motor inputs that differ in structural and functional properties co-innervate most muscles to coordinate locomotion. To stabilize NMJ activity, motor neurons augment neurotransmitter release following diminished postsynaptic glutamate receptor functionality, termed presynaptic homeostatic potentiation (PHP). How these distinct inputs contribute to PHP plasticity remains enigmatic. We have used a botulinum neurotoxin to selectively silence each input and resolve their roles in PHP, demonstrating that PHP is input-specific: Chronic (genetic) PHP selectively targets the tonic MN-Ib, where active zone remodeling enhances Ca2+ influx to promote increased glutamate release. In contrast, acute (pharmacological) PHP selectively increases vesicle pools to potentiate phasic MN-Is. Thus, distinct homeostatic modulations in active zone nanoarchitecture, vesicle pools, and Ca2+ influx collaborate to enable input-specific PHP expression.

Differential functions of phosphatidylinositol 4-kinases in neurotransmission and synaptic development.

Phosphoinositides, such as PI(4,5)P2, are known to function as structural components of membranes, signalling molecules, markers of membrane identity, mediators of protein recruitment and regulators of neurotransmission and synaptic development. Phosphatidylinositol 4-kinases (PI4Ks) synthesize PI4P, which are precursors for PI(4,5)P2, but may also have independent functions. The roles of PI4Ks in neurotransmission and synaptic development have not been studied in detail. Previous studies on PI4KII and PI4KIIIβ at the Drosophila larval neuromuscular junction have suggested that PI4KII and PI4KIIIβ enzymes may serve redundant roles, where single PI4K mutants yielded mild or no synaptic phenotypes. However, the precise synaptic functions (neurotransmission and synaptic growth) of these PI4Ks have not been thoroughly studied. Here, we used PI4KII and PI4KIIIβ null mutants and presynaptic-specific knockdowns of these PI4Ks to investigate their roles in neurotransmission and synaptic growth. We found that PI4KII and PI4KIIIβ appear to have non-overlapping functions. Specifically, glial PI4KII functions to restrain synaptic growth, whereas presynaptic PI4KIIIβ promotes synaptic growth. Furthermore, loss of PI4KIIIβ or presynaptic PI4KII impairs neurotransmission. The data presented in this study uncover new roles for PI4K enzymes in neurotransmission and synaptic growth.

Role of Agrin in tissue repair and regeneration: From mechanisms to therapeutic opportunities (Review).

Tissue regeneration is a complex process that involves the recruitment of various types of cells for healing after injury; it is mediated by numerous precise interactions. However, the identification of effective targets for improving tissue regeneration remains a challenge. As an extracellular matrix protein, Agrin plays a critical role in neuromuscular junction formation. Furthermore, recent studies have revealed the role of Agrin in regulating tissue proliferation and regeneration, which contributes to the repair process of injured tissues. An in‑depth understanding of the role of Agrin will therefore be of value. Given that repair and regeneration processes occur in various parts of the human body, the present systematic review focuses on the role of Agrin in typical tissue and highlights the potential signaling pathways that are involved in Agrin‑induced repair and regeneration. This review offers important insight into novel strategies for the future clinical applications of Agrin‑based therapies, which may represent a feasible treatment option for patients who require organ replacement or repair.

Elevated serum levels of C-terminal agrin fragment in acetylcholine receptor antibody-positive myasthenia gravis

Agrin is essential for neuromuscular junction (NMJ) formation and maintenance. The C-terminal agrin fragment (CAF), generated by neurotrypsin-mediated cleavage of agrin, has been gaining attention as a potential biomarker for sarcopenia. We investigated serum CAF levels in myasthenia gravis (MG), a NMJ disorder. Compared to healthy controls, serum CAF levels were significantly elevated in acetylcholine receptor antibody-positive MG (AChR-MG) patients, but not in muscle-specific kinase antibody-positive MG patients. In AChR-MG, baseline and post-treatment CAF levels inversely correlated with post-treatment MG activities of daily living scores, suggesting that elevated CAF levels may reflect protective mechanisms against AChR-MG pathogenesis, such as improved NMJ regeneration.

Finite Element Modeling of Beam-to-Column Steel Timber Composite Joints with Different Parameters

This study presents a comprehensive three-dimensional finite element modeling and parametric analysis of composite beam-to-column joints in steel–timber composite structures. The investigation encompassed a variety of shear connector configurations, end plate designs, and bolt dimensions, aiming to elucidate their respective influences on the structural performance and behavior of these joints. Through meticulous numerical simulation, this research sought to enhance the understanding of the interactions and load transfer mechanisms within composite connections, thereby contributing to the optimization of design practices in the field of structural engineering. The load–displacement relationship for timber–steel composite joints subjected to monotonic loading was investigated using ABAQUS 6.14 software. This study systematically analyzed the effects of various parameters, including different configurations of shear connectors, end plate thicknesses, and bolt dimensions, on the overall performance of the joints. Through this comprehensive numerical analysis, the research aimed to provide deeper insights into the mechanical behavior and structural integrity of these composite connections under the applied loading conditions. A non-linear finite element model of timber was developed and verified with the results of the experiment in this study. The findings are discussed in detail, highlighting the intricate relationships between the selected parameters and their respective effects on the performance and overall stability of the composite connections. This thorough evaluation aimed to enhance the understanding of how these variables interact within the context of composite joint design and behavior. Finally, design recommendations for composite structures, such as the dimensions of the bolt, end plate thickness, and different sizes of shear connectors are provided.

Non-coding RNA and its network in the pathogenesis of Myasthenia Gravis.

Myasthenia Gravis (MG) is a chronic autoimmune disease that primarily affects the neuromuscular junction, leading to muscle weakness in patients with this condition. Previous studies have identified several dysfunctions in thymus and peripheral blood mononuclear cells (PBMCs), such as the formation of ectopic germinal centers in the thymus and an imbalance of peripheral T helper cells and regulatory T cells, that contribute to the initiation and development of MG. Recent evidences suggest that noncoding RNA, including miRNA, lncRNA and circRNA may play a significant role in MG progression. Additionally, the network between these noncoding RNAs, such as the competing endogenous RNA regulatory network, has been found to be involved in MG progression. In this review, we summarized the roles of miRNA, lncRNA, and circRNA, highlighted their potential application as biomarkers in diagnosing MG, and discussed their potential regulatory networks in the abnormal thymus and PBMCs during MG development.

Moment Capacity of Bolted-Side Plate for the Eaves Joint of Nested Tapered Box Beam Portal Frame

The joints of cold-formed steel (CFS) portal frames with box sections are primarily formed either through stiffened welded connections or by bolted end plates, which typically involve costly full penetration butt welds. In New Zealand, CFS portal frames with nested tapered box beam (NTBB) sections are popular, and the joints of these portal frames are also formed through a bolted end plate system. In literature, it was found that welds in these joints are prone to cracking in the heat-affected zone (HAZ) under bearing opening moments (tension). Therefore, this paper focuses on proposing an alternative connection system (bolted-side plate) for eaves joints without any weld, aiming to reduce the overall cost of construction and increase construction speed. The performance (strength and stiffness) of these joints is mainly dependent on the geometric details of the bolted-side plate, which is limited in Australia/New Zealand standards (AS/NZ 4600). Herein, a non-linear finite element (FE) model was developed for the NTBB portal frame and validated against the experimental test results from the literature. Firstly, the validated FE model was used to investigate the feasibility of using bolted-side plates for NTBB portal frames and found that the bolted-side plate can increase the ultimate capacity of NTBB portal frame by 9%. A parametric study was then conducted by considering different geometric details of the bolted-side plates under both closing (gravity) and opening (wind uplift) moments. Finally, unified design equations for the moment capacity of bolted-side plates were proposed based on the results of the parametric study, and their accuracy was assessed through reliability analysis.

Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.

Ageing is a complex multifactorial process, impacting all organs and tissues, with DNA damage accumulation serving as a common underlying cause. To decelerate ageing, various strategies have been applied to model organisms and evaluated for health and lifespan benefits. Dietary restriction (DR, also known as caloric restriction) is a well-established long-term intervention recognized for its universal anti-ageing effects. DR temporarily suppresses growth, and when applied to progeroid DNA repair-deficient mice doubleslifespan with systemic health benefits. Counterintuitively, attenuation of myostatin/activin signalling by soluble activin receptor (sActRIIB), boosts the growth of muscle and, in these animals, prevents muscle wasting, improves kidney functioning, and compresses morbidity. Here, we investigated a combined approach, applying an anabolic regime (sActRIIB) at the same time as DR to Ercc1Δ/- progeroid mice. Following both single treatments and combined, we monitored global effects on body weight, lifespan and behaviour, and local effects on muscle and tissue weight, muscle morphology and function, and ultrastructural and transcriptomic changes in muscle and kidney. Lifespan was mostly influenced by DR (extended from approximately 20 to 40weeks; P<0.001), with sActRIIB clearly increasing muscle mass (35-65%) and tetanic force (P<0.001). The combined regime yielded a stable uniform body weight, but increased compared with DR alone, synergistically improved motor coordination and further delayed the onset and development of balance problems. sActRIIB significantly increased muscle fibre size (P<0.05) in mice subjected to DR and lowered all signs of muscle damage. Ercc1Δ/- mice showed abnormal neuromuscular junctions. Single interventions by sActRIIB treatment or DR only partially rescued this phenotype, while in the double intervention group, the regularly shaped junctional foldings were maintained. In kidney of Ercc1Δ/- mice, we observed a mild but significant foot process effacement, which was restored by either intervention. Transcriptome analysis also pointed towards reduced levels of DNA damage in muscle and kidney by DR, but not sActRIIB, while these levels retained lower in the double intervention. In muscle, we found synergistic effects of combining sActRIIB with DR, but not in kidney, with an overall better health in the double intervention group. Crucially, the benefits of each single intervention are not lost when administered in combination, but rather strengthened, even when sActRIIB was applied late in life, opening opportunities for translation to human.

Comparative Analysis of Intravenous Immunoglobulins (IVIg) vs Plasmapheresis (PLEX) in the Management of Myasthenic Crisis.

Myasthenia gravis (MG) is an autoimmune disorder affecting postsynaptic membranes in neuromuscular junctions, presenting as fatigable muscle weakness. Myasthenic crisisis a life-threatening complication characterized by severe respiratory insufficiency necessitating invasive or noninvasive ventilation. Two rapid therapiesused to manage myasthenic crisesare intravenous immunoglobulins (IVIg) and plasmapheresis (PLEX). Their comparative effectiveness remains equivocal. Our article examines evidence from several clinical trials and observational studies, in order to determine the superiority of one treatment over the other. Multiple factors can complicate the choices between two treatments. We concluded that the choice between PLEX and IVIg is multifaceted, guided by individual patient characteristics, institutional resources, and clinician preference. While PLEX can be consideredasfirst-linefor rapid clinical outcomes, it is hard to pick one treatment over the other, and careful consideration of comorbiditiesand resource availability is crucial. Our article highlights the need for further research to establish definitive guidelines and enhance patient outcomes in myasthenic crisis patients.

A spinal and bulbar muscular atrophy (SBMA) disease-specific human embryonic stem cell (hESC) line, UMICHe002-A/UM197-1

Spinal and Bulbar Muscular Atrophy (SBMA) is an X-linked degenerative disorder of the neuromuscular system that is caused by an expanded CAG/polyglutamine (polyQ) tract within the Androgen Receptor (AR) gene. This mutation causes progressive muscle weakness and atrophy in men. Here, we report the establishment of the first SBMA disease-specific human embryonic stem cell (hESC) line in the NIH hESC registry, UM197-1. UM197-1 exhibits pluripotency, the ability to differentiate into three germ layers in vitro, and provides a new cellular model system to study SBMA disease pathogenesis.

Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction.

Skeletal muscles are essential for locomotion, posture, and metabolic regulation. To understand physiological processes, exercise adaptation, and muscle-related disorders, it is critical to understand the molecular pathways that underlie skeletal muscle function. The process of muscle contraction, orchestrated by a complex interplay of molecular events, is at the core of skeletal muscle function. Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction. Within muscle fibers, calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force. Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling. The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis. Myogenic regulators coordinate the differentiation of myoblasts into mature muscle fibers. Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability. Several muscle-related diseases, including congenital myasthenic disorders, sarcopenia, muscular dystrophies, and metabolic myopathies, are underpinned by dysregulated molecular pathways in skeletal muscle. Therapeutic interventions aimed at preserving muscle mass and function, enhancing regeneration, and improving metabolic health hold promise by targeting specific molecular pathways. Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway, a critical regulator of myogenesis, muscle regeneration, and metabolic function, and the Hippo signaling pathway. In recent years, more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers, and at the neuromuscular junction. In fact, research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers. In this review, we will summarize and discuss the data on these two pathways, focusing on their concerted action next to their contribution to skeletal muscle biology. However, an in-depth discussion of the non-canonical Wnt pathway, the fibro/adipogenic precursors, or the mechanosensory aspects of these pathways is not the focus of this review.

Lifelong dietary protein restriction induces denervation and skeletal muscle atrophy in mice

As a widespread global issue, protein deficiency hinders development and optimal growth in offspring. Maternal low-protein diet influences the development of age-related diseases, including sarcopenia, by altering the epigenome and organ structure through potential increase in oxidative stress. However, the long-term effects of lactational protein restriction or postnatal lifelong protein restriction on the neuromuscular system have yet to be elucidated. Our results demonstrated that feeding a normal protein diet after lactational protein restriction did not have significant impacts on the neuromuscular system in later life. In contrast, a lifelong low-protein diet induced a denervation phenotype and led to demyelination in the sciatic nerve, along with an increase in the number of centralised nuclei and in the gene expression of atrogenes at 18 months of age, indicating an induced skeletal muscle atrophy. These changes were accompanied by an increase in proteasome activity in skeletal muscle, with no significant alterations in oxidative stress or mitochondrial dynamics markers in skeletal muscle later in life. Thus, lifelong protein restriction may induce skeletal muscle atrophy through changes in peripheral nerves and neuromuscular junctions, potentially contributing to the early onset or exaggeration of sarcopenia.

Sequence analysis, homology modeling, tissue expression, and potential functions of seven putative acetylcholinesterases in the spider Cupiennius salei.

Acetylcholine esterases (AChEs) are essential enzymes in cholinergic synapses, terminating neurotransmission by hydrolysing acetylcholine. While membrane bound AChEs at synaptic clefts efficiently perform this task, soluble AChEs are less stable and effective, but function over broader areas. In vertebrates, a single gene produces alternatively spliced forms of AChE, whereas invertebrates often have multiple genes, producing both enzyme types. Despite their significance as pesticide targets, the physiological roles of invertebrate AChEs remain unclear. Here, we characterized seven putative AChEs in the wandering spider, Cupiennius salei, a model species for neurophysiological studies. Sequence analyses and homology modeling predicted CsAChE7 as the sole stable, membrane-bound enzyme functioning at synaptic clefts, while the others are likely soluble enzymes. In situ hybridization of sections from the spider's nervous system revealed CsAChE7 transcripts co-localizing with choline acetyltransferase in cells that also exhibited AChE activity. CsAChE7 transcripts were also found in rapidly adapting mechanosensory neurons, suggesting a role in precise and transient activation of postsynaptic cells, contrasting with slowly adapting, also cholinergic, neurons expressing only soluble AChEs, which allow prolonged activation of postsynaptic cells. These findings suggest that cholinergic transmission is influenced not only by postsynaptic receptors but also by the enzymatic properties regulating acetylcholine clearance. We also show that acetylcholine is a crucial neurotransmitter in the spider's visual system and sensory and motor pathways, but absent in excitatory motor neurons at neuromuscular junctions, consistent with other arthropods. Our findings on sequence structures may have implications for the development of neurological drugs and pesticides.

Neurotropic Effect of Botulinum Toxin and the Potential of Specific Serum Therapy in Botulism (Review)

INTRODUCTION. The outbreak of foodborne botulism that occurred in Russia in June 2024 once again demonstrated the danger of this rather rare but severe infectious disease caused by ingesting botulinum neurotoxin. The only aetiological treatment for botulism is currently the administration of antitoxins against various serotypes of botulinum toxin. However, antitoxins do not provide rapid regression of neurological symptoms, which may raise doubts about the effectiveness of the selected treatment option. It is impossible to assess the potential of specific treatment without understanding the mechanisms of action of botulinum toxin and antitoxin.AIM. This study aimed to systemise information on the mechanism underlying the damaging effect of botulinum neurotoxin, aetiological antitoxin treatment, and the patient recovery process.DISCUSSION. The mechanism underlying the damaging effect of botulinum neurotoxin consists in the destruction of SNARE proteins in presynaptic cholinergic nerve terminals, which disrupts the release of acetylcholine into the synaptic cleft and the transmission of excitation between neurons. The lack of acetylcholine at the neuromuscular junction results in a distinctive form of persistent flaccid paralysis. The specific mechanism of action of botulinum toxin determines the treatment strategy, which includes a set of life-sustaining measures and the earliest possible antiserum administration. If used within 48 hours from the onset of symptoms, botulinum antitoxin binds botulinum toxin circulating in the blood, which stops the progression of paralysis and prevents further disorders in patients. However, botulinum antitoxin cannot neutralise the effect of the toxin that has already bound to nerve receptors, so clinical symptoms may worsen within 12 hours after antiserum administration. Restoration of normal neuronal transmission occurs through the formation of new axonal sprouts and can take a long time.CONCLUSIONS. Antitoxin administration is effective and irreplaceable in the aetiological treatment of botulism. Nevertheless, the duration of recovery depends on the speed of reinnervation and restoration of transmission at the neuromuscular junction.

Characterization of Clinical Phenotypes in Congenital Myasthenic Syndrome Associated with the c.1327delG Frameshift Mutation in CHRNE Encoding the Acetylcholine Receptor Epsilon Subunit.

Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.

A Nonlinear Analysis of Nociceptive Flexion Reflex Changes Before and After Acute Inflammation

Objectives: The nociceptive flexion reflex (NFR) is used as a pseudo-objective measure of pain that is measured using electromyography (EMG). EMG signals can be analyzed using nonlinear methods to identify complex changes in physiological systems. Physiological complexity has been shown to allow a wider range of adaptable states for the system to deal with stressors. The purpose of this study was to examine changes in complexity and entropy of EMG signals from the biceps femoris during non-noxious stimuli and noxious stimuli that evoked the NFR before and after acute inflammation. Methods and Materials: Twelve healthy participants (25.17y ± 3.43) underwent the NFR protocol. EMG signal complexity was calculated using Hurst Exponent (H), determinism (DET), and recurrence rate (RR), and Sample Entropy (SampEn). Results: RR (∼200%), DET (∼70%), and H (∼35%) were higher and SampEn was reduced (∼50%) during the noxious stimulus that evoked the NFR compared to non-noxious stimuli. No significant differences were found for any of the complexity and entropy measures before and after exercise-induced inflammation (p<0.05). Reduced complexity (increased H, DET, and RR) and increased regularity (SampEn) reflect reduced adaptability to stressors. Conclusions: Nonlinear methods such as complexity and entropy measures could be useful in understanding how a healthy neuromuscular system responds to disturbances. The reductions in complexity following a noxious stimulus could reflect the neuromuscular system adapting to environmental conditions to prevent damage or injury to the body.

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

EVs move messes, not messages, at the synapse.

Extracellular vesicles are known for intercellular signaling roles but can also serve to simply dispose of unwanted cargoes. In this issue, Bostelman and Broihier discuss new work from Rodal and colleagues (https://doi.org/10.1083/jcb.202405025) that refutes prior work by showing that extracellular vesicles at Drosophila neuromuscular junctions are not required for signaling and instead likely serve a proteostasis role.